The long range goal of this project is to identify genetic mutations that predispose the schizophrenia. Data from family, twin and adoption studies speak for a genetic predisposition, and if the molecular basis of these findings can be uncovered it may lead us to the pathophysiology of the disease process itself. The strategy is to use multiplex pedigrees of schizophrenia for three types of genetic investigation. First, candidate genes for schizophrenia will be examined in a genetic linkage design, using polymorphic DNA probes to genotype multiplex pedigrees. Second, pedigrees from this project will be pooled in a collaborative effort using the human gene map in a systematic effort to find disease genes. We will be collaborating with the Utah group, and if we are selected as a pedigree collection center for the NIMH gene bank we will collaborate on that effort as well. The third approach we propose is dictated by the definite possibility that schizophrenia may be too heterogeneous to find disease genes by either of the above two methods. This possibility calls for a research strategy that is based on individual pedigrees, where one is dealing with a single mutation, rather than on pooled pedigree sets. We propose sequencing careful selected candidate genes in probands from multiplex pedigrees using the polymerase chain reaction for genomic DNA amplification and an automated sequencer for obtaining the sequence data. The pedigrees will be used to determine whether any sequence variations found cosegregate with the disease. We propose to begin with the dopamine D2 receptor because of its key role in schizophrenia.